PLUNC is a novel protein that was identified in differential display analysis whose function is just being elucidated. PLUNC is produced by tracheal epithelial cells and secreted into the airways where it is present in high concentrations in all mammals. PLUNC has structural similarities to LPS binding proteins and recent studies indicate that it has antimicrobial functions. Our studies are the first to establish that PLUNC also has anti-inflammatory effects, distinct from its antimicrobial effects. In studies where PLUNC is inhibited by intranasal siRNA, increased eosinophilia was observed in naive mice and mice with Th2 inflammation. We show that PLUNC is regulated by both TLR signals and IFN-[unreadable], indicating that both microbial and inflammatory pathways control its expression. These findings suggest that PLUNC may serve as a gatekeeper of inflammation in the lung. In this proposal we will: (I) Define the functions of PLUNC in innate and adaptive immune responses using PLUNC deficient and PLUNC overexpressor mice that have a range of pulmonary inflammatory responses, including those induced by Th1, Th2, Th17 and Treg cells, TLR-agonists, and in models of chronic airway inflammation. (II) Determine the mechanisms by which PLUNC regulates immunity by assessing how PLUNC influences eosinophilia in the lung. (III) Define factors that modulate PLUNC by further investigating TLR and IFN-[unreadable] pathways of PLUNC inhibition and testing different anti-inflammatory mediators for stimulatory effects on PLUNC. These studies will provide insights into immunity in the respiratory tract and may reveal novel pathways by which to modulate inflammation to aid in control of infections and inflammatory diseases. PLUNC is a recently discovered protein that is present in high concentrations in the secretions that bathe the respiratory tract. PLUNC is present in all mammals, yet its functions have not been fully elucidated. Our early studies show that PLUNC regulates inflammation in the lung to protect us from harmful infections. In the proposed experiments we will determine what the precise effects of PLUNC are and how it acts to perform these important functions.